Appearance
4.3 — Fertilisation to Blastocyst: the First Week
An egg is the largest cell in the human body — about 100 to 120 micrometres across, just visible to the naked eye as a speck. A sperm is one of the smallest, about 5 micrometres in the head, and it is essentially a nucleus with a propeller and a fuel supply. The egg contributes all the cytoplasm, all the mitochondria, and all the machinery. The sperm contributes DNA, a centriole, and a signal that starts everything.
One of roughly 200 to 300 million sperm reaches the egg. The rest is arithmetic, chemistry and timing, and understanding it explains contraception, infertility treatment, and why ectopic pregnancy is a surgical emergency.
Getting there
The journey. Sperm are deposited in the vagina and must reach the outer third of the fallopian tube, a distance of about 15 to 18 centimetres. For a cell 5 micrometres long, that is proportionally like a person swimming several kilometres.
Attrition is enormous at every stage. Most sperm never leave the vagina, whose acidity — pH around 4 — kills them within hours. Semen is alkaline and buffers this briefly, which is a large part of what it is for. Of those entering the cervix, the mucus filters out abnormal shapes mechanically. Cervical mucus changes across the cycle: for most of the month it is thick and hostile, and around ovulation it becomes thin, watery and arranged in channels that guide sperm through. That change is the basis of natural family planning methods and of one mechanism by which the progesterone-only pill works — it thickens the mucus so sperm cannot pass.
Of the millions starting, a few hundred to a few thousand reach the fallopian tubes, and only a few dozen reach the egg.
Sperm are not fertile when they arrive. They must undergo capacitation — several hours of exposure to the female tract during which cholesterol is stripped from the sperm membrane, making it unstable and ready to fuse, and the tail switches to a violent whip-like beat that generates the force needed to push through the egg's coverings. This is why sperm cannot fertilise an egg immediately after ejaculation, and it is a step that has to be reproduced artificially in the laboratory for IVF to work.
Timing is tight. An egg survives about 12 to 24 hours after ovulation. Sperm survive about 3 to 5 days in the female tract, occasionally longer. So the fertile window is roughly five days before ovulation and one day after — about six days per cycle. Intercourse after ovulation has ended contributes almost nothing.
Fertilisation itself
Reaching the surface. The egg is surrounded by two layers: an outer cloud of follicle cells called the corona radiata, and beneath it a thick glycoprotein shell, the zona pellucida. Sperm push through the corona, then bind a specific receptor protein on the zona — species-specific binding, which is one reason cross-species fertilisation generally fails.
The acrosome reaction. Binding triggers the sperm's acrosome, a lysosome-like cap on its head, to release enzymes that digest a channel through the zona.
Fusion, and the block to polyspermy. The first sperm to reach the egg membrane fuses with it. Fusion immediately triggers a wave of calcium release inside the egg, and that wave does three things within seconds to minutes.
It causes granules just under the egg membrane to release their contents into the zona, chemically hardening it so no further sperm can bind or penetrate. This is the block to polyspermy, and it is essential — two sperm entering gives a cell with 69 chromosomes, which never develops into a viable pregnancy and usually produces a molar pregnancy, an abnormal placental growth that requires removal and follow-up because a small proportion become malignant.
It also completes the egg's meiosis, which had been arrested in metaphase II since ovulation, discarding the extra chromosome set as a small polar body.
And it switches the egg's metabolism on. The egg had been essentially dormant; fertilisation activates it.
The two nuclei — now called pronuclei — approach, their envelopes break down, and the chromosomes combine on a single spindle. This is the moment a diploid human genome exists, and the cell is now a zygote.
Sex is determined here. The egg always carries an X. The sperm carries either an X or a Y, and which one arrives decides it (Chapter 2.7).
The first week
Cleavage. The zygote divides — but it does not grow. Each division halves the cell size rather than doubling the mass, because the whole structure is still enclosed in the zona pellucida and there is no external food supply. The egg's stored materials are being divided up.
Day 1: two cells. Day 2: four. Day 3: eight. Day 4: about sixteen, now a solid ball called a morula, from the Latin for mulberry.
Around the eight-cell stage the cells stick together tightly for the first time — compaction — and for the first time they are no longer equivalent. Cells on the outside and cells on the inside now experience different environments, and that difference is the first decision made in a human body.
The blastocyst. Around day 5, fluid is pumped into the centre and the ball hollows out.
Two populations now exist and their fates are already separate.
The trophoblast — the outer shell — becomes the placenta and fetal membranes. It never becomes part of the body.
The inner cell mass — a cluster of maybe 20 to 30 cells at one pole — becomes the entire embryo. These are the cells that are pluripotent (Chapter 1.7), and they are the source of embryonic stem cells, which is precisely why that research is ethically contested: obtaining them destroys the blastocyst.
Hatching. Around day 5 to 6 the blastocyst breaks out of the zona pellucida, which it must do because implantation requires direct contact with the uterine lining.
Implantation
Around day 6 to 7, the blastocyst attaches to the endometrium — the uterine lining, which has been thickening under hormonal instruction since the last period ended (Chapter 15.4).
The trophoblast becomes invasive. It digests its way into the lining, and its outer layer fuses into a single multinucleated sheet that erodes maternal blood vessels, creating pools of maternal blood that the developing placenta will draw from. By around day 10 to 12 the embryo is completely buried within the lining.
This invasion is deliberately restrained, and when the restraint fails there is disease. Too shallow an invasion means the maternal arteries supplying the placenta are not adequately remodelled, the placenta is underperfused, and the result is pre-eclampsia — a pregnancy complication of high blood pressure and organ damage that remains a leading cause of maternal death worldwide (Chapter 15.6). Too deep an invasion, usually into a previous caesarean scar, gives placenta accreta, where the placenta will not separate at delivery and can cause catastrophic bleeding.
The trophoblast begins producing hCG — human chorionic gonadotropin — almost immediately. Its job is to tell the ovary's corpus luteum to keep producing progesterone, which keeps the uterine lining in place. Without hCG the lining would shed on schedule and the pregnancy would be lost before it was known.
hCG is what a pregnancy test detects. It is detectable in blood from around 8 to 11 days after ovulation and in urine a few days later, which is why a home test is reliable from around the first missed period and unreliable before it. Levels roughly double every 48 to 72 hours in early pregnancy, and that doubling rate is itself a diagnostic tool — a slow rise suggests either a failing pregnancy or an ectopic one.
When implantation happens in the wrong place
Ectopic pregnancy is implantation outside the uterine cavity, and about 95 percent occur in a fallopian tube. It affects roughly 1 to 2 percent of pregnancies.
The tube cannot accommodate a growing embryo. It has no capacity to expand and no proper blood supply for a placenta. As the pregnancy grows, the tube stretches and eventually ruptures — into a space full of major blood vessels.
This is one of the genuine surgical emergencies of early pregnancy, and it is still a leading cause of maternal death in the first trimester. The classic presentation is a woman of reproductive age with abdominal pain, a missed period and vaginal bleeding, though the presentation is often less clear-cut than that. The rule that saves lives is that any woman of reproductive age with abdominal pain gets a pregnancy test, without exception, because a ruptured ectopic can present as collapse with no bleeding visible externally — the blood is all inside the abdomen. Chapter 15.6.
Risk factors are anything that damages the tube: previous pelvic infection, previous ectopic, tubal surgery, and — importantly — an intrauterine contraceptive device, which prevents uterine implantation very effectively and therefore raises the proportion of the few pregnancies that occur which are ectopic, while reducing the absolute number of both.
Twins, and why the timing matters
Fraternal (dizygotic) twins come from two eggs fertilised by two sperm. They are ordinary siblings sharing a womb, no more genetically alike than any other pair of siblings. The rate varies with maternal age, family history and — most significantly today — fertility treatment.
Identical (monozygotic) twins come from one zygote splitting. The rate is about 3 to 4 per 1,000 births and is remarkably constant across populations, which suggests it is essentially random rather than inherited.
When the split happens determines everything about the pregnancy's risk.
Before day 4 (before the trophoblast has committed): each twin gets its own placenta and its own sac. Lowest risk.
Days 4 to 8 (after the trophoblast has formed but before the amniotic sac): the twins share a placenta but have separate sacs. This is about two thirds of identical twins, and it introduces a specific danger — twin-to-twin transfusion syndrome, where blood vessel connections within the shared placenta are unbalanced, so one twin receives too much blood and the other too little. Both can die without intervention, and treatment is laser ablation of the connecting vessels in the womb.
Days 8 to 13: shared placenta and shared sac. Higher risk still, because the cords can tangle.
After day 13: the split is incomplete, producing conjoined twins.
So "identical twins" describes several quite different clinical situations, and establishing which one a pregnancy is by ultrasound in the first trimester determines how closely it is monitored. This is one of the more consequential pieces of information in obstetrics and it can only be determined early — the membranes become harder to assess as pregnancy advances.
What IVF actually does
Worth stating because it maps exactly onto the steps above.
Eggs are collected after stimulating the ovaries to mature several follicles rather than one. Sperm are prepared and capacitated artificially, since the female tract is being bypassed. Fertilisation happens either by mixing the two in a dish, or — where sperm quality is poor — by ICSI, in which a single sperm is injected directly into the egg with a fine needle, bypassing the zona and the acrosome reaction entirely.
The resulting embryos are cultured to the blastocyst stage, assessed, and one is transferred into the uterus. Transferring one rather than several is now standard practice, because multiple pregnancy is the single largest risk of fertility treatment, both to the mother and to the babies.
Robert Edwards received the 2010 Nobel Prize for developing IVF; Louise Brown, the first person conceived this way, was born in 1978, and over ten million people have now been conceived by these methods.
What the next page fixes
The blastocyst has two cell populations and no body plan — no head, no tail, no front, no back, no tissues. Chapter 4.4 covers the two weeks in which all of that appears: gastrulation, the formation of the three germ layers, and the master table of which layer becomes which organ, which is the single most useful thing to know in all of embryology.